We currently are investigating COMT, Dysbindin, BDNF, ARC, NRG, BAD, KCNH2 and the gene-gene interaction of COMT/Dysbindin. We have demonstrated conclusively with genetically altered mice the effect of COMT on psychiatric relevant behaviors, including on cognition, emotional arousal, pain sensitivity and amphetamine response. Increased COMT activity is a risk factor for cortically dependent cognitive dysfunctions but a protective factor in stressful situations, whereas COMT reduction enhances working memory processes but results in exaggerated stress reactivity. The generated COMT transgenic mice (overexpressing a human COMT-val), and compared them with mice containing a null COMT mutation. COMT transgenic and knock-out mice mimicked salient aspects of human behaviors associated with COMT polymorphisms, and established the biologic validation of these associations. Our COMT model reifies that a common genetic factor can be involved in diverse clinical disorders characterized by abnormal cognitive processing and stress reactivity and represents a promising new animal model for testing cognitive and stress related therapies. In this context, the need for an established strategy for biological validation is important. CBDB/GCAP investigators have developed neuroimaging methods to confirm at a biological level clinical evidence of epistatic interactions within genes and between genes and have extended these findings to signaling within lymphoblast cell lines and in animal models involving breeding of genetically altered mouse strains. Our transgenic mice overexpressing human COMT-val (Val-tg) was compared with mice without a functional COMT and normal mice which contain COMT-leu. Increased COMT activity in Val-tg mice resulted in impaired attentional set shifting abilities, and working and recognition memory. There was no change in acquisition or reversal learning. COMT Val-tg mice also showed recognition memory deficits. However, acute treatment with amphetamine, which increases dopamine levels, restored recognition memory performance in COMT Val-tg mice but worsened performance control. Despite the COMT genotype effects on working memory processes, COMT Val-tg mice showed normal performance in tasks involving a regularly repeated sequence of events rather than trial-specific experience. These results highlight the COMT gene as a critical factor in the regulation of executive memory processes. With regards to environmental stressors, COMT null mice ( -/-) were the best performers under low stress conditions, whereas COMT heterozygous mice (+/-) performed best under challenging conditions. It appears that mild uncontrolled stress impairs PFC working memory functions in human and animals. We have demonstrated that increased COMT activity is a risk factor for cortically dependent cognitive dysfunctions but a protective factor when under stress, whereas COMT reduction enhances working memory processes but results in exaggerated stress reactions. The COMT transgenic and knock-out mice show notable aspects of human behaviors associated with COMT mutations and establish biologic validity of these associations. Our COMT mouse model establishes that a common genetic factor can be involved in diverse clinical disorders characterized by abnormal cognitive processing and reaction to stress which represents a promising new animal model for testing cognitive and stress related therapies. Finally, these results demonstrate an intriguing functional trade-off between genetic variation that concurrently results in more efficient cognitive behaviors and less adaptive affective behaviors.